PPARs in Health and Disease

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 6015

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Guest Editor
Department of Pharmacology, Faculty of Medicine, University of Ioannina, Ioannina 45110, Greece
Interests: drug metabolism; PPARα; stress systems biology; neural plasticity; antipsychotics in cancer
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Special Issue Information

Dear Colleagues,

Peroxisome proliferator-activated receptors (PPARs) belong to a nuclear receptor superfamily, acting as ligand-activated transcription factors that exert specific pleiotropic responses. The three known isoforms, PPARα, PPARβ/δ, and PPARγ, hold, among others, determinant roles in energy homeostasis, regulating glucose and lipid metabolism. Upon binding with hormones, lipids, or other ligands, PPARs act by forming heterodimers with retinoic X receptors and, in cooperation with co-repressors or co-activators, regulate several target genes. They are involved in the pathophysiology of metabolic disorders and are pharmaceutical targets for their treatment. Specifically, PPARα and PPARγ agonists are used in the treatment of hyperlipidemia and type 2 diabetes, respectively. It also appears that activation of PPARs affects carcinogenesis because it can be involved in the complex regulation of cancer cell type-specific proliferation, differentiation, and survival. In the last decade, intensive research has focused on the potential role of PPARα, PPARγ, and PPARβ/δ specific agonists in the improvement of brain cell metabolism and cognitive function in neurodegenerative and neurodevelopmental disorders. PPARs also regulate morphogenesis and inflammatory response. This Special Issue of Biomedicines includes the most recent advances in the regulation and function of PPARs and provides well-grounded views on therapeutic perspectives for the use of PPAR agonists or antagonists in various disease states, including dyslipidemia, atherosclerosis, obesity, diabetes, neurodegenerative disorders, and cancer.

Prof. Dr. Maria Konstandi
Guest Editor

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Keywords

  • PPARα
  • PPARβ/δ
  • PPARγ
  • nuclear receptor
  • lipid homeostasis
  • glucose homeostasis
  • neurodegenerative disorders
  • dyslipidemia
  • atherosclerosis
  • cardiovascular disease
  • cancer

Published Papers (3 papers)

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Research

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15 pages, 2585 KiB  
Article
Oleuropein Promotes Neural Plasticity and Neuroprotection via PPARα-Dependent and Independent Pathways
by Foteini Malliou, Christina E. Andriopoulou, Aristeidis Kofinas, Allena Katsogridaki, George Leondaritis, Frank J. Gonzalez, Theologos M. Michaelidis, Marousa Darsinou, Leandros A. Skaltsounis and Maria Konstandi
Biomedicines 2023, 11(8), 2250; https://doi.org/10.3390/biomedicines11082250 - 11 Aug 2023
Cited by 1 | Viewed by 2236
Abstract
Oleuropein (OLE), a main constituent of olives, displays a pleiotropic beneficial dynamic in health and disease; the effects are based mainly on its antioxidant and hypolipidemic properties, and its capacity to protect the myocardium during ischemia. Furthermore, OLE activates the peroxisome proliferator-activated receptor [...] Read more.
Oleuropein (OLE), a main constituent of olives, displays a pleiotropic beneficial dynamic in health and disease; the effects are based mainly on its antioxidant and hypolipidemic properties, and its capacity to protect the myocardium during ischemia. Furthermore, OLE activates the peroxisome proliferator-activated receptor (PPARα) in neurons and astrocytes, providing neuroprotection against noxious biological reactions that are induced following cerebral ischemia. The current study investigated the effect of OLE in the regulation of various neural plasticity indices, emphasizing the role of PPARα. For this purpose, 129/Sv wild-type (WT) and Pparα-null mice were treated with OLE for three weeks. The findings revealed that chronic treatment with OLE up-regulated the brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the prefrontal cortex (PFC) of mice via activation of the ERK1/2, AKT and PKA/CREB signaling pathways. No similar effects were observed in the hippocampus. The OLE-induced effects on BDNF and TrkB appear to be mediated by PPARα, because no similar alterations were observed in the PFC of Pparα-null mice. Notably, OLE did not affect the neurotrophic factors NT3 and NT4/5 in both brain tissues. However, fenofibrate, a selective PPARα agonist, up-regulated BDNF and NT3 in the PFC of mice, whereas the drug induced NT4/5 in both brain sites tested. Interestingly, OLE provided neuroprotection in differentiated human SH-SY5Y cells against β-amyloid and H2O2 toxicity independently from PPARα activation. In conclusion, OLE and similar drugs, acting either as PPARα agonists or via PPARα independent mechanisms, could improve synaptic function/plasticity mainly in the PFC and to a lesser extent in the hippocampus, thus beneficially affecting cognitive functions. Full article
(This article belongs to the Special Issue PPARs in Health and Disease)
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20 pages, 4717 KiB  
Article
PPARα Inhibits Astrocyte Inflammation Activation by Restoring Autophagic Flux after Transient Brain Ischemia
by Doudou Luo, Wenxuan Ye, Ling Chen, Xiaoqian Yuan, Yali Zhang, Caixia Chen, Xin Jin and Yu Zhou
Biomedicines 2023, 11(3), 973; https://doi.org/10.3390/biomedicines11030973 - 21 Mar 2023
Cited by 3 | Viewed by 1805
Abstract
Astrocyte inflammation activation is an important cause that hinders the recovery of motor function after cerebral ischemia. However, its molecular mechanism has not yet been clearly clarified. The peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated nuclear transcriptional factor. This study aims to [...] Read more.
Astrocyte inflammation activation is an important cause that hinders the recovery of motor function after cerebral ischemia. However, its molecular mechanism has not yet been clearly clarified. The peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated nuclear transcriptional factor. This study aims to further clarify the role of PPARα in astrocyte inflammation activation after cerebral ischemia and to explore the underlying mechanism. Astrocyte activation was induced in an in vivo model by transient middle cerebral artery occlusion (tMCAO) in mice. The in vitro model was induced by an oxygen-glucose deprivation/reoxygenation (OGD/R) in a primary culture of mouse astrocyte. PPARα-deficient mice were used to observe the effects of PPARα on astrocyte activation and autophagic flux. Our results showed that PPARα was mainly expressed in activated astrocytes during the chronic phase of brain ischemia and PPARα dysfunction promoted astrocyte inflammatory activation. After cerebral ischemia, the expressions of LC3-II/I and p62 both increased. Autophagic vesicle accumulation was observed by electron microscopy in astrocytes, and the block of autophagic flux was indicated by an mRFP-GFP-LC3 adenovirus infection assay. A PPARα deficit aggravated the autophagic flux block, while PPARα activation preserved the lysosome function and restored autophagic flux in astrocytes after OGD/R. The autophagic flux blocker bafilomycin A1 and chloroquine antagonized the effect of the PPARα agonist on astrocyte activation inhibition. This study identifies a potentially novel function of PPARα in astrocyte autophagic flux and suggests a therapeutic target for the prevention and treatment of chronic brain ischemic injury. Full article
(This article belongs to the Special Issue PPARs in Health and Disease)
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Review

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21 pages, 731 KiB  
Review
Peroxisome Proliferator-Activated Receptor α in Lipoprotein Metabolism and Atherosclerotic Cardiovascular Disease
by Elena Valeria Fuior, Evangelia Zvintzou, Theodosios Filippatos, Katerina Giannatou, Victoria Mparnia, Maya Simionescu, Anca Violeta Gafencu and Kyriakos E. Kypreos
Biomedicines 2023, 11(10), 2696; https://doi.org/10.3390/biomedicines11102696 - 3 Oct 2023
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Abstract
Peroxisome proliferator-activated receptors (PPARs) are a group of ligand-binding transcription factors with pivotal action in regulating pleiotropic signaling pathways of energetic metabolism, immune responses and cell proliferation and differentiation. A significant body of evidence indicates that the PPARα receptor is an important modulator [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) are a group of ligand-binding transcription factors with pivotal action in regulating pleiotropic signaling pathways of energetic metabolism, immune responses and cell proliferation and differentiation. A significant body of evidence indicates that the PPARα receptor is an important modulator of plasma lipid and lipoprotein metabolism, with pluripotent effects influencing the lipid and apolipoprotein cargo of both atherogenic and antiatherogenic lipoproteins and their functionality. Clinical evidence supports an important role of PPARα agonists (fibric acid derivatives) in the treatment of hypertriglyceridemia and/or low high-density lipoprotein (HDL) cholesterol levels, although the effects of clinical trials are contradictory and point to a reduction in the risk of nonfatal and fatal myocardial infarction events. In this manuscript, we provide an up-to-date critical review of the existing relevant literature. Full article
(This article belongs to the Special Issue PPARs in Health and Disease)
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